Tumor molecular targeted therapy is a treatment method based on the key molecules closely related to the tumor growth through chemical or biological means so as to selectively kill tumor cells. Targeted therapy is characterized by high specificity, strong selectivity and mild side effects; when used in combination, it can enhance the efficacy of traditional chemotherapy, radiotherapy, and reduce postoperative recurrence. Tumor targeted therapy is a hotspot and trend of tumor therapy.
Protein tyrosine kinases (PTKs) are a class of protein enzymes that catalyzes the phosphorylation of phenolic hydroxyl groups on tyrosine residues of various important proteins, thereby activating the function of functional proteins. Studies have shown that more than half of proto-oncogenes and oncogenes are associated with protein tyrosine kinases. The research of anti-tumor drugs with tyrosine kinases as a target becomes a hotspot in the world, and is also the focus of the research of pharmaceutical development institutions.
Epidermal growth factor receptor (EGFR), a receptor tyrosine protein kinases, regulates cell proliferation, survival, adhesion, migration and differentiation. EGFR is over activated or constitutively activated in various tumor cells, such as lung cancer, breast cancer, prostate cancer and so on. Blocking the activation of EGFR and Erb-B2 is clinically confirmed as a dominant approach to targeted therapy of tumor cells. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, have been get a quick approval of US FDA for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have lost response to conventional chemotherapy.
Multiple prospective clinical studies have confirmed that EGFR-TKI (EGFR-tyrosine kinases inhibitors) response rate in NSCLC patients with EGFR activated mutation positive is significantly higher than that in NSCLC patients with EGFR wild-type, while progression-free survival (PFS) and overall survival (OS) also significantly prolonged. Nevertheless, PFS of the majority of patients with EGFR mutation positive is no more than 12 to 14 months, that is to say, resistance to TKI has been occurred in them. The mechanism of acquired resistance and its clinical coping strategies is another hotspot in the field of targeted therapy.
For drug resistance, the strategy used in clinical practice is: Strategy 1: continue to use EGFR-TKI, cross-use gefitinib and erlotinib. In short, continue using TKI after the TKI progress is of some, but very limited benefits. Strategy 2: Developing new EGFR-TKI. Strategy 3: treating for other target sites. As the “alternative pathway” plays an important role in EGFR-TKI resistance, targeted drugs for these pathways are continuously appearing. However, currently the EGFR-TKI is still unable to solve the clinical stress caused by drug resistance, and most of the existing drugs are EGFR reversible or irreversible inhibitor in which the basic nucleus is quinazoline or quinoline amine, and the toxic side effects caused by the poor selectivity for wild-type cells are also unavoidable.
Therefore, there is an urgent need to provide new types of compounds, particularly novel skeletons, to solve problems such as drug resistance, poor selectivity, and poor pharmacological properties.